Chapter 2 - University of British Columbia

4.1 Introduction
Genetic alterations play a significant role in a variety of malignancies [1, 2]. Typically, these
alterations have been represented by either changes in gene dosage (DNA copy number) or
somatic mutations such as total copy number gain or activating mutations of oncogenes and
total copy number loss or inactivating mutations of tumor suppressor genes. Loss of
heterozygosity is also a common alteration whereby one allele is lost and often, results in a loss
of total copy number. However, there are instances in which where one allele is lost but the
remaining allele is duplicated resulting in no net change in copy number, termed copy neutral
loss of heterozygosity or somatic uniparental disomy (UPD).
Although somatic UPD had been shown previously in malignancies such as retinoblastoma [3],
recent studies have shown an increased prominence of this alteration [4]. This largely been a
result of advances in technology to detect somatic UPD and advances in the methodologies to
define UPD [5, 6]. Moreover, frequent regions of somatic UPD have been identified in many
different cancer types such as colorectal cancer [7, 8], lymphoma [9, 10], myelodysplastic
syndrome (MDS) [11-13], basal cell carcinoma [14], hepatoblastoma [15], and ovarian cancer
[16]. In addition, while the target gene of some of these regions have been associated to tumor
suppressors such as RB1 and TP53, where the gene is likely mutated, the targets have also
been associated with oncogenes. For example, mutation with somatic UPD has been observed
at loci such as JAK2 [6, 17], CBL [12, 18], FLT3 [19] in hematological malignancies. However,
such associations have been limited in epithelial malignancies.
Recently, we have illustrated the concept of mutant allele specific imbalance (MASI) in lung
cancer [20]. It was found that a highly activated state for EGFR and KRAS is achieved through
either copy number amplification of the mutated allele for EGFR and UPD of the mutated allele
for KRAS. With the observed frequency of UPD at KRAS as such, we sought to assess the
impact and prevalence of UPD in the lung adenocarcinoma genome. Strikingly, we found that
the amount of the genome affected frequently by UPD was comparable to that of copy number
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